Production and post-surgical modification of VEGF, tPA and PAI-1 in patients with glioma

Malignant gliomas are associated with risk of thromboembolism, but the molecular link between tumor and peripheral pro-coagulant status has not been elucidated. Vascular Endothelial Growth Factor (VEGF), tissue-type Plasminogen Activator (tPA), Plasminogen Activator Inhibitor-1 (PAI-1) and lipoprotein (lp) (a) influence the pro-coagulant status. To assess whether the presence of the tumor influenced the peripheral levels of VEGF, tPA, PAI-1 and lp(a), we studied the expression and secretion of VEGF, tPA, PAI-1 and lp(a) in glioma specimens, in peripheral blood and in primary glioma-derived cultures. We also measured lp(a), VEGF, tPA and PAI-1 in the peripheral circulation of patients, before and after surgery for glioma. VEGF, tPA and PAI-1 were expressed in glioma specimens. Glioma cells were indeed a major source of tPA and PAI-1; these molecules were significantly more expressed in glioma than in patient's blood cells. Lp(a) was rarely expressed in glioma specimens and not expressed in blood cells. In glioma, VEGF, tPA and PAI-1 were localized mainly in tumor cells; tPA was localized also in the extracellular matrix and PAI-1 in tumor vascular lumen. Glioma cells were indeed able to produce and release VEGF, tPA and PAI-1. After surgery, peripheral levels of VEGF and PAI-1 were increased, while tPA and lp(a) were unchanged. The great amount of VEGF, tPA and PAI-1 produced by glioma could influence peripheral levels of these molecules. The partial resection of the tumor by surgery was not able to decrease plasma levels of these molecules.     

Growth hormone secretion in prepubertal children with major depression. III. Response to insulin-induced hypoglycemia after recovery from a depressive episode and in a drug-free state

Insulin tolerance tests (ITTs) were performed after at least four months of sustained recovery from an episode of a major depressive disorder in 18 drug-free prepubertal children. Eleven had a definite endogenous subtype; seven did not. Sixteen children with nondepressed neurotic disorders made up a control group. The children with past endogenous depression continued to have significant hyposecretion of growth hormone (GH) in this test when compared with the other groups. Illness-recovery correlations were highly significant for the major depressive group as a whole. Paired comparisons of both depressive groups were not significantly different from illness to recovery. We conclude that prepubertal children with endogenous major depression continue to have hyposecretion of GH in response to ITTs in a recovered state and that this neuroendocrine marker is state independent. A GH hyporesponse to ITT may be a true marker of a past episode or of trait for endogenous major depressive disorder in prepuberty.     

Enhancement of carrageenin foot oedema by 1,10-phenanthroline and evidence for the bradykinin as endogenous mediator

Carrageenin oedema is enhanced by the simultaneous injection in the rat paw of 1,10-phenanthroline, a kininase inhibitor. The analysis of the time-course of this enhancement showed that the maximal effect was observed about 3 hours after the injection. This enhancement was also present when the oedemaproducing agent was cellulose sulphate, a kinin-releasing compound. On the contrary, oedema induced by eggwhite as well as by dextran, which are mainly mediated by histamine and 5-hydroxytryptamine, were unaffected by 1,10-phenanthroline. These results further support the role of kinins in the pathogenesis of carrageenin oedema.     

BCR/ABL P190 transgenic mice develop leukemia in the absence of Crkl

The Bcr/Abl fusion protein directly causes chronic myelogenous leukemia and Philadelphia-chromosome positive acute lymphoblastic leukemia. Multiple independent studies have implicated Crkl, a small adapter protein, in transduction of oncogenic signals of Bcr/Abl and Crkl tyrosine-phosphorylation is used as a diagnostic tool for Philadelphia-positive leukemia. To evaluate the contribution of Crkl to this type of leukemia, we generated mutant mice that lack Crkl expression. We found that the overall survival of P190 BCR/ABL crkl-/- mice was comparable to that of genetically matched P190 BCR/ABL crkl +/+ mice. Both genotypes developed lymphoid lineage leukemia/lymphoma. Western blot analysis of -/- and +/+ lymphomas showed that the related Crk protein was tyrosine phosphorylated and could be found complexed with Bcr-Abl P190. These data indicate that possible therapeutic approaches that target Crkl may be complicated by the presence of pathways that compensate for lack of Crkl function.     

Distinct expression of cyclooxygenase-1 and -2 in the human thymus

Cyclooxygenase (COX)-1 and -2 catalyze the formation of prostaglandins (PG). Given the role of COX and PG during intrathymic T cell development in the mouse, we investigated the expression and localization of these isozymes in the human thymus. mRNA and proteins correspondent to COX-1 and -2 were observed from whole thymus extracts. By immunohistochemistry, COX-2 was selectively localized in the medulla and it was predominant in a subset of stromal cells. By contrast, COX-1 was diffusely and exclusively present in the cortex, both in thymocytes at early stages of differentiation and in cytokeratin-positive epithelial cells, as demonstrated by double immunostaining and flow cytometry analysis. COX-2-positive cells in the medulla expressed cytokeratin and HLA-DR molecules, but they were negative for dendritic or macrophagic antigens. In addition, COX-2-positive cells expressed both the epidermal growth factor receptor and its ligand, the transforming growth factor-alpha. The inducible isoform of the PGE(2) synthase was also present in the same cells, while was absent from COX-1-expressing cells of the cortex. Finally, electron microscopy confirmed that COX-2 was mainly localized in the cytoplasm of cytokeratin-positive cells, along the rough endoplasmic reticulum. In conclusion, COX-2 and the inducible isoform of PGE(2) synthase appear to be constitutively and selectively present in medullary epithelial cells of the human thymus, whereas COX-1 is predominantly present in the thymic cortex, both in the stroma and in developing thymocytes.     

Red wine consumption and inhibition of LDL oxidation: what are the important components?

The 'French Paradox' has been attributed to the regular drinking of red wine. The beneficial effects of red wine could be related to both the alcohol and antioxidant activities of red wine polyphenols. However, it is not clear whether the alcohol component is important and the results of intervention trials are conflicting. In the present report, we have examined the polyphenol composition of red wines used in the various studies and have suggested a few possible reasons for discrepancies in their effects on lipoprotein oxidation.     

A comparison of female and male rats' ETOH-induced ataxia and exploration following restraint or swim stress

Animal models of stress reactivity are often employed in developing treatments for humans. Many studies use shock stress, and most use male rats. These experiments compare female and male rats exposed to either restraint stress (RS) or ambient-temperature swim stress (SS), using two durations of each stressor and naive controls. The ataxic effects of a 0.6 g/kg i.p. dose of ethanol (ETOH) were measured. Females exhibited less ataxia than males following ETOH administration. There were no significant effects of stress on ETOH-induced ataxia. Exploration was also measured in an open-field test (OFT) both pre- and poststress. In the prestress OFT, females were more active than males. For the no-stress groups and the shorter-duration stress groups, exploration decreased between the first and second OFTs. However, the groups exposed to the longer-duration stress did not show this expected decrease in exploration. A key finding of this research is that while sex differences may be present at baseline, the sexes may react similarly to stress. These data extend knowledge on sex differences in stress, alcohol reactivity and exploratory behavior.     

LOCALIZATION AND FUNCTIONS OF SP-A AND SP-D AT MUCOSAL SURFACES

Pulmonary surfactant protein A (SP-A) and D (SP-D), members of the collectin family, are implicated in innate host defense of the lung. Collectins consist of a collagen-like domain and a carbohydrate recognition domain. SP-A and SP-D recognize and interact with glycoconjugates on the surface of microorganisms. They protect the lung by interacting with a wide variety of potential pathogens, including viruses, bacteria, and fungi. This may result in enhanced killing and/or clearance by phagocytes. Although most extensively studied in the lung, both SP-A and SP-D, or proteins closely resembling SP-A and SPD, are found in a number of other sites in the body and therefore may play a protective role at other sites than the lung. SP-A and SP-D protein and/or mRNA have been detected at various sites of the body: the respiratory tract, the gastrointestinal tract, the middle ear, and in the peritoneal cavity. The presence of SP-A and SP-D at these mucosal surfaces, in close contact with numerous potentially harmful microorganisms, supports a role for these "lung"-collectins in innate mucosal defense. SP-A and SP-D may be important molecules in a threefold innate defense, particularly in the neonatal period between maternally acquired immunity and a fully developed adaptive immune system; the time interval between first exposure to a pathogen and generation of specific antibodies; and states of impaired immune function.